Depression is a common and harmful mood disorder that affects emotion, cognition, and behaviour; rather than a clearly defined disease, depression involves a wide spectrum of disorders ranging from the feeling of unhappiness to more severe incapacitating disorders such as Clinical depression (also called major-depressive disorder or unipolar depression), Dysthymic disorder, Bipolar disorder, Atypical depression, Psychotic depression, Postpartum depression and Seasonal affective disorder (A. Doris et al. Depressive illness, Lancet, 1999, 354, 9187, 1369). According to the World Health Organization (WHO), depression is characterized by depressed mood, loss of interest or pleasure, feelings of guiltiness or low-self-esteem, disturbances in sleep and/or appetite, poor concentration. Major depressive disorder, also known as major depression, is the most common type of depression with about 10-25% lifetime risk in the industrialized countries population. It is characterized by a combination of symptoms and disabling conditions that seriously interfere with work and family life, sleeping and eating habits, and with the general health of the patient. Dysthymic disorder, also called dysthymia, is characterized by long-term less severe symptoms that may not disable a person but can prevent a person of feeling well thus impacting the social life. Bipolar disorder, also called manic-depressive illness, is characterized with cycling mood changes from extreme highs (e.g., mania) to extreme lows (e.g., depression). Atypical Depression is a subtype of dysthymia and major depression characterized by mood reactivity and vegetative symptoms like over-eating and over-sleeping. Psychotic depression, occurs when a severe depressive illness is accompanied by some form of psychosis, hallucinations, and delusions. Postpartum depression, which affects 10-15% of women, is diagnosed if a major depressive episode occurs within one month after the childbirth, the disease has similar symptoms as clinical depression. Seasonal affective disorder, is characterized by the onset of a depressive illness during the winter months. Depressive and anxiety symptoms often overlap. Anxiety disorders comprise post-traumatic stress disorder, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder. Panic disorder is classified as an anxiety disorder since anxiety is the predominant symptom, panic attacks are discrete episodes consequence of a panic disorder. The development of severe phobic symptoms matches the escalation in frequency and intensity of panic attacks, leading to a severe and disabling disorder which impacts the patient professional, social and familial life. Depression may be a primary condition or can co-exists with other serious medical illnesses such as heart disease, stroke, cancer, diabetes and Parkinson's disease. Clinical studies have shown that people who have depression in addition to another serious medical illness tend to have more severe symptoms of both depression and the medical illness, more difficulty adapting to their medical condition, and more medical costs than those without co-existing depression. Research has provided evidences that treating the depression can also help at improving the outcome of treating the co-occurring illness. Alcohol, tobacco and drug abuse may also co-occur with depression. In fact, statistical research indicated that the co-existence of mood disorders is pervasive among the people involved in alcohol, tobacco and drug abuse. Depressive disorders are extremely common, affecting about 120 million people worldwide each year. According to WHO depression is a leading cause of disability and it is the fourth most important contributor to the global burden of disease. Morbidity and mortality in depressed patients are higher than in normal subjects. According to the National Institute of Mental Health (NIMH) recent studies highlighted how persons with major depression were four times as likely to suffer of a heart attack as not depressed controls. According to NIMH direct and indirect social costs of depression amounted for the year 1990 to about 30 billion USD, being indirect costs represented by decreased worker productivity and disruption of personal, professional and family relationships. An analogue evaluation in Europe for year 2004 high-lighted a social cost of 118 billion Euro, pointing out depression as the most costly brain disorder in Europe.
According to the monoamine hypothesis, depression is caused by an imbalance of these neurotransmitters in the brain. One pharmacological strategy aimed at overcoming this imbalance consists of inhibiting the enzyme Monoamine Oxidase (MAO; EC 1.4.3.4). The monoamine neurotransmitters serotonin (5-HT), norepinephrine (NE) and dopamine are widely distributed within the brain and are involved in the regulation of mood, cognition, sleep, anxiety and social behavior. Dysfunctions in mechanisms controlling these neurotransmitters are often associated with most major psychiatric disorders and drugs targeting monoamine neurotransmitters have been and are widely investigated for the treatment of depression. MAO is a FAD dependent enzyme (flavoprotein) mainly located in outer mitochondrial membranes of neurons and glial cells as well as in other cells of the periphery (i.e.: epatocytes), where it catalyzes the oxidative deamination of neurotransmitter, xenobiotic and endogenous amines. The antidepressant approach for MAO inhibitors is based on the fact that by inhibiting the enzyme activity, deactivation of these endogenous neurotransmitters is prevented thus increasing both their synaptic concentration and duration of action. There are two isoforms of MAO: MAO-A which preferentially deaminates serotonin, norepinephrine and epinephrine, but also amines present in foods like tyramine, and MAO-B which preferentially deaminates dopamines, phenylethylamines and benzylamines (B. H. Moussa, British J. Pharmacolgy, 2006, 147, S287-296). The first generation of MAO inhibitors not selectively and irreversibly blocked both MAO isoforms this led to side-effects such as hypertensive crisis (also called “chese syndrome”) especially due to MAO-A inhibition, that blocking tyramine metabolism trigger a cascade in which excessive amounts of norepinephrine can lead to a hypertensive crisis. Second generation MAO-A reversible inhibitors such as moclobemide and brofaromin displayed in clinical trials potent antidepressant activity but a negligible propensity to induce after ingestion of tyramine, hypertensive crisis at the therapeutic dosage (Bonnet U., CNS Drug review, 2003, 9, 1, 97-140). This because reversibility allows competition and thus ingested tyramine is able to displace the inhibitor from the enzyme. MAO-B selective reversible inhibitors do not give rise to hypertensive crisis. Recent studies provide evidence that also anxiety disorders may be linked to malfunction in serotonine neurotransmission and unbalances in catecholamine metabolism. Efficacy of MAO inhibitors in the treatment of anxiety disorders has been demonstrated by several clinical trials and case reports (J. Clin. Psychiatry, 2006, 67, S12:20-26). Inhibitors of MAO-B prolong the activity of both endogenously and exogenously derived dopamine, making them an option either as monotherapy in early Parkinson's disease (PD) or as add-on therapy in patients treated with levodopa. Efficacy of the MAO-B approach for the PD treatment was clinically proved by trials involving the two US approved MAO-B inhibitors Rasagiline and Selegiline as well as using Safinamide, at the present in phase III. All these drugs provided symptomatic relief when used as monotherapy or as adjunctive therapy, even displaying potential as disease-modifying agents.
Imidazoline receptors, a family of non-adrenergic receptors, first identified by Bousquet in 1984, are widely distributed both centrally and peripherally. Three main subclasses of imidazoline binding sites (IBS) have been identified: I1-IBS, which preferentially binds clonidine, is located on the membrane of neurones and is involved in the central blood pressure regulation, I2-IBS, which preferentially binds idazoxan, is located principally in the outer membrane of mitochondria, and I3-IBS that has been identified in the pancreas. Protein isolation studies have shown that MAO-A and MAO-B are both I2 binding proteins. Further pharmacological studies demonstrated how agonists at I2-IBS are able to inhibit MAO activity thus providing an alternate approach to MAO inhibitors for controlling the activity of both MAO-A and MAO-B. It was shown in several animal models how I2-IBS ligands are able to modulate central monoamine levels, as well as it has been recently shown how alterations in I2-IBS density can be highlighted in depressed patients. Agmantine is an endogenous amine, formed by arginine decarboxylation, which has been proposed as a neurotransmitter in the CNS. Recently for Agmantine and other selective I2-IBS agonists such as 2-BFI (2-benzofuranylimidazoline) and norharman (β-carboline) antidepressant properties in several animal models have been reported, thus confirming in vivo that I2-imidazoline receptor is a new pharmacological target for the treatment of depression and related disorders (M P Zeidan, Eur. J. Pharmacology, 2007, 565, 1-3, 125-31).
Narcotic and alcohol withdrawal is often accompanied by atypical depression which give rise to resumption of alcohol or narcotics, accordingly antidepressant treatment including treatment with MAO inhibitors can generally be considered as a pharmacological approach to treat narcotic and alcohol abuse. However in some cases MAO inhibitors have been proven by preclinical or clinical trials even superior than other anti-depressive drugs for several reasons.
Nicotine induces tollerance and addiction by acting on the central dopaminergic pathways, thus only 50% reduction in nicotine consumptions may trigger withdrawal symptoms such as anxiety, depressive symptoms, cognitive disorders, sleep disorders. The use of MAO inhibitors as a new pharmacotherapy for the treatment of smoking dependence is based upon both the compensation effect of these drugs on the dopaminergic pathway and to the anti-depressive effects that should avoid remission episodes (T. P. George et al., Clin. Pharmacol Ther., 2008, 83, 4, 619-21).
Cocaine abuse is a serious health problem in many areas of the world, up to date there are no approved pharmacological treatments to overcome cocaine dependence. Preclinical studies suggest that cocaine dependence may be due to dopamine transporter inhibition exerted by cocaine, which give rise to a dopamine reinforced effect. MAO inhibitors and particularly MAO-B inhibitors, as proved by preliminary trials with the MAO-B inhibitor selegiline, increasing the monoamine levels can help in overcoming cocaine dependence counteracting the dopamine level drop due to the drug withdrawal (E. J. Houtsmeller, Psychopharmacology, Berl., 2004, 172, 1, 31-40).
Preclinical models highlighted how I2-IBS ligands enhances analgesic action of morphine and inhibits tollerance and dependence to opioids (A. Mirales et al., Eur. J. Pharmacology, 2005, 22, 518, 2-3, 234-242). Agmantine and 2-BFI along with other I2-IBS agonists have been shown to potentiate opioid induced analgesia and to attenuate the development of tolerance and dependence, while I2-IBS antagonist such as idazoxan completely reversed these effects. Interestingly, the same effects of potentiation of morphine analgesia and prevention of tollerance and dependence was observed in animal models also with MAO inhibitors (A Wasik et al., J. Physiol. Pharmacol., 2007, 58, 2, 235-52; K Grasing et al., Behav Pharmacol., 2005, 16, 1, 1-13), and confirmed clinically for Moclobemide, a reversible MAO-A inhibitor (G. Vaiva, Prog. Neuropsychopharmacol Biol. Psychiatry, 2002, 26, 3, 609-11).